title: Ranolazine recruits muscle microvasculature and enhances insulin action in rats.
abstract: Ranolazine, an anti-anginal compound, has been shown to significantly improve glycaemic control in large-scale clinical trials, and short-term ranolazine treatment is associated with an improvement in myocardial blood flow. As microvascular perfusion plays critical roles in insulin delivery and action, we aimed to determine if ranolazine could improve muscle microvascular blood flow, thereby increasing muscle insulin delivery and glucose use. Overnight-fasted, anaesthetized Sprague-Dawley rats were used to determine the effects of ranolazine on microvascular recruitment using contrast-enhanced ultrasound, insulin action with euglycaemic hyperinsulinaemic clamp, and muscle insulin uptake using (125)I-insulin. Ranolazine's effects on endothelial nitric oxide synthase (eNOS) phosphorylation, cAMP generation and endothelial insulin uptake were determined in cultured endothelial cells. Ranolazine-induced myographical changes in tension were determined in isolated distal saphenous artery. Ranolazine at therapeutically effective dose significantly recruited muscle microvasculature by increasing muscle microvascular blood volume (∼2-fold, P < 0.05) and increased insulin-mediated whole body glucose disposal (∼30%, P = 0.02). These were associated with an increased insulin delivery into the muscle (P < 0.04). In cultured endothelial cells, ranolazine increased eNOS phosphorylation and cAMP production without affecting endothelial insulin uptake. In ex vivo studies, ranolazine exerted a potent vasodilatatory effect on phenylephrine pre-constricted arterial rings, which was partially abolished by endothelium denudement. In conclusion, ranolazine treatment vasodilatates pre-capillary arterioles and increases microvascular perfusion, which are partially mediated by endothelium, leading to expanded microvascular endothelial surface area available for nutrient and hormone exchanges and resulting in increased muscle delivery and action of insulin. Whether these actions contribute to improved glycaemic control in patients with insulin resistance warrants further investigation.
authors.affiliation: Z. Liu: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, PO Box 801410, Charlottesville, VA 22908, USA. zl3e@virginia.edu.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fu
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Weidong
authors.initials: W
authors.lastname: Chai
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Dong
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D014463:Ultrasonography; D014664:Vasodilation
chemical_list: D000083:Acetanilides; D001786:Blood Glucose; D007328:Insulin; D010879:Piperazines; D000069458:Ranolazine; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III